Suppression of homeobox transcription factor VentX promotes expansion of human hematopoietic stem/multipotent progenitor cells.

Mechanisms that regulate proliferation and expansion of human hematopoietic stem/multipotent progenitor cells (HSC/MPPs) are targets of intensive investigations. Several cell intrinsic factors and signaling pathways have been implicated in the proliferation and differentiation of human HSC/MPPs. Nevertheless, expansion of human HSC/MPPs for clinical application remains a critical challenge. VentX is a human homeobox transcription factor that was recently identified as an anti-proliferation and pro-differentiation factor in human hematopoietic cells. Here, we report that VentX expression is up-regulated during ontogenesis of human hematopoietic cells. Strikingly, suppression of VentX expression led to significant expansion of HSC/MPPs ex vivo and a 20-fold increase in engraftment potential in the NOD/SCID/IL2Rγ2(null) mouse model. VentX suppression helped preserve the HSC/MPP pools and promote clonogenicity of hematopoietic progenitor cells. Mechanistically, we show that VentX regulates critical cell cycle regulators and Wnt downstream genes previously implicated in HSC/MPP proliferation and expansion.

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